Head and neck squamous cell carcinoma (HNSCC) is the 6th most common type of cancer. Survival rates for advanced disease are poor, and treatment leads to impairment in speech, hearing, swallowing, and quality of life. The goal of our laboratory is to improve upon treatments for HNSCC by increasing their efficacy and decreasing toxicity. Standard treatments including cisplatin and other platinum-based chemotherapy drugs and radiation. Immune checkpoint inhibitors have also recently been FDA approved for the treatment of HNSCC. One major goal of the lab is to determine how cisplatin chemotherapy affects the immune system, in order to best design treatment paradigms that include new immunotherapy drugs or novel agents targeting specific mutations in HNSCC. Other goals include characterizing the toxicities of cisplatin chemotherapy in HNSCC patients, with a focus on characterizing and preventing cisplatin-induced hearing loss. Previous preclinical studies in the lab have established that cisplatin alters specific aspects of anti-tumor immunity, including antigen processing and presentation. Another project has established that cisplatin chemotherapy may also induce a process called immunogenic cell death (ICD), whereby cells upon treatment release damage signals and activate anti-tumor immunity. In work completed and published this year we demonstrated that some damage signals are induced by platinum chemotherapy. Additional experiments showed that vaccination of mice with tumor cells killed by platinum chemotherapy induces ICD, thereby prevent tumor growth when living tumor cells are later introduced. A third project involves the study of immune mechanismss of a novel targeted anti-cancer drug, the IAP inhibitor ASTX660. Work from previous years established that ASTX660 enhances anti-tumor immunity, in part via natural killer cells, CD8+ T cells, and TNF alpha. TMore recent experiments in the lab are focusing on possible immune effects of ASTX660 on tumor cells, including antigen processing and immunogenic cell death. These data have been submitted for publication. The goal of this project is to determine whether ASTX660 may be a less toxic alternative to chemotherapy for the treatment of HNSCC. Another focus is the characterization and prevention of hearing loss in HNSCC patients treated with cisplatin. Cisplatin is known to cause permanent damage to mechanosensory hair cells and other structures of the inner ear, causing high-frequency hearing loss. Patients with HNSCC are at particular risk, since many are treated with cisplatin as well as radiation near the inner ear. Intramural collaborations have been established within NIDCD to investigate the incidence and severity of cisplatin-induced hearing loss and effects of cholesterol-lowering statin drugs in HNSCC patients treated with low-dose weekly cisplatin combined with radiation. A clinical study in collaboration with Johns Hopkins University is currently underway.